Method for delaying the onset of, or postponing, parturition

ABSTRACT

This invention relates to the administration of 2-(6substituted-2-naphthyl)acetic and propionic acids, and salts, esters and other derivatives thereof, to pregnant mammals for delaying the onset of, or postponing, parturition.

United States Patent [191 Henzl et al.

[ METHOD FOR DELAYING THE ONSET OF,

OR POSTPONING, PARTURITION [75] Inventors: Milan R. ll-lenzl, Palo Alto; Adolph Roszkowski, Saratoga, both of Calif.

[73] Assignee: Syntex Corporation, Panama,

Panama [22] Filed: Mar. 29, 1973 [21] Appl. No.: 345,878

US. Cl. 424/308, 424/317 lnt. Cl A61k 27/00 Field of Search 424/308, 317

[561 References Cited UNITED STATES PATENTS 3,562,336 2/1971 Nelson .1 260/613 1 Mar. 25, N75

Primary Examiner-Sam Rosen Attorney, Agent, or Firm-Joseph l. Hirsch; William B. Walker [57] ABSTRACT This invention relates to the administration of 2-(6- substituted-Z-naphthyl)acetic and propionic acids, and salts, esters and other derivatives thereof, to pregnant mammals for delaying the onset of, or postponing, parturition.

10 Claims, N0 Drawings METHOD FOR DELAYING THE ONSET OF, ()R POSTPONING, PARTURITION BRlEl SUMMARY OF THE INVENTION This invention relates to the use of 2-( o-substituted- Z'naphthyH-acetie and propionic acids, salts, esters and other derivatives thereof as agents for maintaining the pregnancy of pregnant mammals until such time as parturition is medically considered to be favorable for the mother and/or the fetus. More particularly, this invention relates to the use of such compounds as agents for delaying the onset of, or postponing, parturition.

The compounds useful in this invention are represented by the following formula:

where R is alkyl having up to 8 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl having up to 7 carbon atoms, trifluoromethyl, vinyl, ethynyl, halo, (iodo, bromo, chloro or fluoro), alkoxy having up to 6 carbon atoms, difluoromethoxy, alkoxymethoxy having up to 7 carbon atoms, alkylthiomethoxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, di-

fluoromethylthio, acetyl, alkoxymethylthio having,

up to 7 carbon atoms, alkylthiomethylthio having up to 7 carbon atoms, cyano, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms;

one of R and R is hydrogen, the other being hydrogen, methyl, ethyl or difluoromethyl or R and R together are methylene or difluoromethylene;

R is hydrogen, alkyl having up to 22 carbon atoms, unsaturated alkyl having up to 22 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 9 carbon atoms, Z-cycloalkylethyl having from to 10 carbon atoms, 3-cyclopentylpropyl, 3-cyclohexylpropyl, benzyl, 2-phenylethyl, 3-phenylpropyl, l,2-dihydroxypropyl, l,3dihydroxypropyl, or 1,2-alkylenedioxypropane having from 4 to 9 carbon atoms and the pharmaceutically acceptable salts of those compounds where R is H.

Preferably, the o'substituent (represented by R in the above formula) is methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, ethoxy, methoxymethoxy, difluoromethoxy, methylthio, ethylthio, methoxymethylthio, difluoromethylthio or phenyl; one of R and R is hydro gen and the other is methyl; and R is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, hexyl, Z-hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, cyclopentyl or cyclohexyl.

The term alkyl refers to and includes branched and straight chain hydrocarbons. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, neopentyl, isopcntyl, hexyl, octyl, nonyl, isodecyl, o-methyldccyl, tridecyl, isotetradecyl, pentadeeyl, isohexadccyl, heptadecyl, cicosyl, docosyl, and the like. The term unsaturated alkyl" refers to unsaturated hydrocarbon groups such as vinyl, allyl, propenyl. erotyl, isopropenyl, 2-propynyl, l-propenyl, Z-butenyl, [,fl-butztdienyl, Z-pentenyl, 2-penten-4-ynyl and the like.

The term cycloalkyl" refers to cyclo hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term alkoxy refers to straight or branched chain alkyl ether groups such as methoxy, ethoxy, 2- propoxy, butoxy, 3-pent0xy and the like.

The term alkoxymethyl refers to methyl groups substituted with one alkoxy group (defined above) such as methoxymethyl, ethoxymethyl, isopropylmethyl, and the like.

The term alkoxymethoxy" refers to methyl ether groups substituted with one alkoxy group (defined above) such as methoxymethoxy, ethoxymethoxy, isopropoxymethoxy and the like.

The term *alkylthio" refers to straight or branched chain alkylthio ether groups such as methylthio, ethylthio, propylthio, Z-propylthio, Z-butylthio, pentylthio, 3-hexylthio and the like.

The term alkylthiomethoxy refers to methyl ether groups substituted with an alkylthio group (defined above) such as methylthiomethoxy, 2- propylthiomethoxy, pentylthiomethoxy and the like.

The term alkylthiomethylthid as used herein denotes methylthio ether groups substituted with an alkylthio group such as methylthiomethylthio, ethylthiomethylthio and the like.

The term alkoxymethylthio refers to methylthio ether groups substituted with an alkoxy group such as methoxymethylthio. ethoxymethylthio, 2- propoxymethylthio and the like.

The term cycloalkylmethyl" refers to cycloalkyl substituted methyl groups such as cyclopropylmethyl. cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like. The term 2- cycloalkylethyl refers to an ethyl group substituted at the 2-position with a cycloalkyl group such as 2- cyclopropylethyl, Z-cyclobutylethyl, 2- cyclopentylethyl, 2-cyclohexylethyl 2- cycloheptylethyl.

The term pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable nontoxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, Zinc, manganous, aluminum, ferric, manganic salts and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, tertiary and quaternary amines. substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as triethylamine, tripropylamine. ethanolamine.

and

2-dimethylaminoethanol. diethylaminoethanol, lysine. arginine. histidine. caffeine, procaine, N-ethylpiperidine. hydrabamine, choline, betaine, ethylenediamine, glucosamine. methylglucamine, theobromine. purines, piperazine. piperidine, polyamine resins and the like.

When one of R and R is hydrogen and the other is methyl, ethyl or difluoromethyl, the compounds of Formula I exist as pairs of enantiomorphs. Each enantiomorph or optical isomer and mixtures thereof are included within the present invention. The compounds of Formula I which exist as pairs of enantiomorphs can be administered as racemic mixtures or they can be administered as resolved enantiomorphs. In some instances, one enantiomorph exhibits greater activity than the other corresponding enantiomorph.

The optical isomers can be resolved by conventional means, such as selective biological degradation or by the preparation of diastereo-isomer salts of the carboxylic acid with an optically active amine base such as cinchonidine and separating the diastereo-isomer salts are then acid cleaved to yield the respective optical isomers.

In the broadest sense, the compounds described above are useful as agents for maintaining the pregnancy of pregnant mammals, for the benefit of the mother and/or the fetus, until termination of the pregnancy is considered, from a medical point of view, to be favorable, or more favorable, for the mother and/or the fetus. It should be understood, however, that in certain instances, for example where parturition has already begun (i.e., the mother is experiencing uterine contractions, especially near full term), that administration of the compounds herein described may not maintain the pregnant state for an indefinite period of time. Rather, in such instances, the pregnancy will, most probably, be slightly prolonged, a factor which may be advantageous to either the mother and/or the fetus.

In particular, the compounds described above are used as agents for delaying the onset of, or for postponing, parturition. As used in this application, the phrase to delay the onset of parturition is intended to cover that delay in parturition caused by the administration of the compounds described above at any time before uterine muscle contractions have begun. Thus, it is intended thatthe aforementioned phrase cover abortion prevention early in pregnancy (i.e., before the fetus is viable) as well as delaying premature parturition, a term which sometimes is used with reference to that premature labor experienced later in the pregnancy when the fetus is considered to be viable. In either case, the agents are administered as prophylatic agents in that such administration tends to prevent the onset of parturition. This administration is particularly useful in the treatment of women having a history of spontaneous abortion, miscarriage or premature delivery (i.e., delivery prior to full term). Such administration is also useful where there are clinical indications that the pregnancy might be terminated prior to that time considered favorable to the mother and/or fetus.

With respect to animals, this treatment can also be utilized to synchronize the deliveries from a group of pregnant animals to happen at or about the same time, or to happen at or about a desired time and/or place, when the births can be handled with greater facility.

As used in this application, the phrase postponing parturition is intended to cover that delay in parturition caused by the administration of the compounds described above after uterine muscle contractions have begun. The condition of the patient, including the time within the gestation period when the contractions have begun, the severity of the contractions and how long the contractions have taken place will affect the results achieved with the administration of the compounds described above. For example, the effect can be to reduce the intensity and/or the duration of the contractions (the actual act of parturition being prolonged), or to stop the contractions altogether. In either case, the effect will be to prolong the gestation period although, depending upon the condition of the patient described above, the effect may either be slight or, under appropriate circumstances, somewhat greater. Such administration may be to prevent spontaneous abortion, to cause the delivery to be more easily accomplished and/or less painful to the mother, or to occur at a more appropriate time and/or place.

In all cases, administration of the compounds described above, for the purposes set forth herein, should be consistent with best and/or accepted medical (or veterinary) practices so to maximize the benefits to the mother and the fetus. For example, administration should not be continued so long past full term that the fetus'dies in utero.

In the practice of the methods of the present invention, a therapeutically effective amount of a compound, as defined above, or a pharmaceutical composition containing a compound as defined above, is administered to the pregnant mammal via any ofthe usual and acceptable methods known in the art. The com pound can be administered either singly or in combination with another compound or compounds, as defined above, or other pharmaceutical agents, carriers, adjuvants, etc. Such compound(s) or compositions can be administered orally, parenterally, or per 05, either in the form of solid, semi-solid, or liquid dosage forms. Typically, administration is by a pharmaceutical composition containing the pharmaceutically active compound and one or more pharmaceutical carriers or adjuvants.

The administration pharmaceutical composition may take the form of oral tablets, vaginal or uterine tablets or suppositories, pills, capsules, liquid solutions, suspensions, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. Conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. The active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier. Liquid pharmaceutically administerable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical com position to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifing agents, pH buffering agents and the like, for example, sodium acetate. sorbitan monolaurate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known. or will be apparent, to those skilled in this art: for example. see Remingtons Pharmaceutical Sciences. Mack Publishing Company, Easton, Pa., 14th. Edition, 1970. The composition or formulation to be administered will. in any event, contain a quantity of the active compound( 5) in an amount effective to delay the onset of parturition or to postpone parturition if uterine contractions have already begun. Generally a daily dose of from 5 mg. to about 50 mg. of the active compound per kilogram of body weight will be administered, with administration being a single daily dose or up to 3 or 4 smaller doses regularly given throughout the day. The aforementioned daily dose is applicable for d-2-(6-methoxy- 2-maphthyl)propionic acid and other compounds described above having activities or potencies substantially equivalent thereto. The daily dose for compounds having substantially different activities from d-2-(6- methoxy-2-naphthyl)-propionic acid may differ from the aforementioned range. generally in a manner reflecting the difference in relative activities.

The active compounds (as defined above) utilizable in the methods of the present invention can be prepared accordingly to the methods described in application Ser. No. l76,740. filed Aug. 31, 1971; and US. Pat. Nos. 3,65l,l06; 3,652,683; 3,658,858; 3,658,863; 3,663,584; 3,686,238; and other patents, assigned to the assignee of this invention, which describe further processes for preparing these compounds. In certain instances, it may be preferred, or desirable, as indicated above, to utilize the biologically active enantiomorph as the agent to be administered. Processes for the isolation of such an enantiomorph are described, for example, in the applications and/or patents listed above in this paragraph.

DESCRIPTION OF SPECIFIC EMBODIMENTS The following specific description is given to enable those skilled in this art to more clearly understand and practice the present invention. It should not be considered as a limitation upon the scope of the invention but merely as being illustrative and representative thereof.

EXAMPLE I A solution is prepared having 100 mg. of d-2-(6- methoxy-Z-naphthyl)propionic acid suspended per ml. of normal saline solution.

EXAMPLE II-III Example I is repeated except dl-2(6-methoxy 2- naphthyI)-propionic acid and l2'(6-methoxy-2-naphthyl)propionic propionic acid are respectively substituted for the d-2-(6-methoxy-2-naphthylpropionic acid of Example I.

EXAMPLE IV Example I is repeated except the saline vehicle additionally contains 0.1% Tween 80 (sorbitan monooleate polyoxyethylene; a product of Atlas Chemical Indus- The above ingredients are thoroughly mixed and pressed into single scored tablets.

The above ingredients are mixed intimately and pressed into single scored tablets.

EXAMPLE VII Ingredients Quantity per capsule, mgs.

2-(6-methyl-2-naphthyl)- 250 acetic acid cornstarch 38 lactose to 380 The above ingredients are mixed and introduced into a hard-shell gelatin capsule.

EXAMPLE VIII Ingredients Quantity per capsule. mgs.

The sodium salt of d 2-(6- 300 methoxy-2-naphthyl)propionic acid lactose 72 magnesium stearate 8 The above ingredients are mixed and introduced into a hard-shell gelatin capsule.

EXAMPLE IX An injectable solution buffered to a pH of 8.5 is prepared having the following composition:

d-2-(6-methoxy-2-naphthyl) propionic acid 2 g. K HPO bufier (0.4 M solution) 2 ml. KOH (1N) 8.6 ml. Water (sterile) to 20 ml.

EXAMPLE X A suppository totaling 2.8 grams is prepared having the following composition:

propionic acid l50500 mg.

Witepsol H- l 5 balance (triglycerides of saturated vegetable fatty acids; a product of Riches-Nelson. Inc. New York. NY.)

Illustrative compounds represented by the formula set forth above include the dlracemic mixture. the disomer, the l-isomer, and the aforementioned salts of:

2-(6-methoxy-2-naphthyl )propionic acid. 2-(6-ethoxy-2-naphthyl )propionic acid. 2-(6-methyl-2-naphthyl )propionic acid. 2-(6-ethyl-2-naphthyl)propionic acid. 2-(6-isopropyl-2-naphthyl)propionic acid.

(i-cyclo ropyl-Lnaphthyl)propionic acid, -(o-vinyl-Z-naphthyl)propionic -(6-ethynyl-2-naphthyl)propionic acid, -(6-chloro-2-naphthyl)propionic acid, 6-fluoro-2-naphthyl)propionic acid, -(6-methylthio-2-naphthyl)propionic acid, -(6-trifluoromethyl-2-naphthyl)propionic acid, 2-(o-difluoromethoxy-Z-naphthyl)propionic acid, 2-(o-difluoromethylthio-2-naphthyl)propionic acid, 2-(fi-difluoromethoxy-Z-naphthyl)-3,3-

difluoropropionic acid, 2-( 6-methylthio-2-naphthyl )-3 ,3-difluoropropionic acid, 2-(6-methoxy-2-naphthyl)-3,3-difluoropropionic acid, 2-(6-methyl-2-naphthyl)-2,3-difluoropropionic acid, isopentyl-2-(6-methoxy-2-naphthyl)propionate, and glycerol 2-(6-methoxy-2-naphthyl)propionate.

Other illustrative compounds include: 2-(6-methoxy-2-naphthyl)acetic acid, 2-(o-ethoxy-l-naphthyl)acetic acid, -(6methyl-2-naphthyl)acetic acid, -(6-ethyl-2-naphthyl)acetic acid, -(6-methylthio-2-naphthyl)acetic acid, -(6-chloro-2-naphthyl) acetic acid,

6-fluoro-2naphthyl)acetic acid,

6-difluoromethylthio-Z-naphthyl)acetic acid,

6-trifluoromethyl-2-naphthyl)acetic acid, -(6-isopropyl-2-naphthyl)acetic acid, 2-(6-cyclopropyl-2-naphthyl)acetic acid, 2-(6-vinyl-2-naphthyl)acetic acid, 2-(6-ethynyl-2-naphthyl)acetic acid, and the pharmaceutically acceptable salts thereof.

The compounds described above are known compounds which have previously been administered in the treatment of inflammation, pyrexia and/or pain. The present invention, however, makes the administration of such compounds applicable to pregnant mammals, particularly women, not suffering from such conditions. for the purposes as set forth herein.

While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in this art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material or composition of matter, process, process step or steps, or then-present objective to the spirit of this invention without departing from its essential teachings.

What is claimed is:

l. A method comprising administering to a pregnant mammal a compound selected from the group of compounds represented by the formula: I

COOR

where R is alkyl having up to 8 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl having up to 7 carbon atoms, trifluoromethyl. vinyl, ethynyl, halogen, alkoxy having up to 6 carbon atoms, difluoromethoxy, alkoxymethoxy having up to 7 carbon atoms, alkylthiomethoxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, difluoromethylthio, acetyl, alkoxymethylthio having up to 7 carbon atoms, alkylthiomethylthio having up to 7 carbon atoms, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms:

one of R and R is hydrogen. the other being hydrogen, methyl, ethyl or difluoromethyl, or R and R together are methylene or difluoromethylene;

R is hydrogen, alkyl having up to 22 carbon atoms, unsaturated alkyl having up to 22 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 9 carbon atoms. 2-cycloalkylethyl having from 5 to 10 carbon atoms, 3-cyclopentylpropyl, 3-cyclohexylpropyl. benzyl, Z-phenylethyl or 3-phenylpropyl: and the pharmaceutically acceptable salts of those compounds where R is H; said compound being administered in a therapeutically effective amount adapted to delay the onset of parturition or to postpone parturition.

' 2. The method of claim 1 wherein said pregnant mammal is a woman who is not suffering from inflammation, pyrexia, or pain, said compound being administered in a therapeutically effective amount adapted to delay the onset of parturition.

3. The method ofclaim 2 wherein said pregnant woman has had a spontaneous abortion. miscarriage or premature delivery which occurred prior to the time for normal parturition at or about full term.

4. The method of claim 2 wherein said compound is dl-2-(6-methoxy-2-naphthyl)propionic acid. I

5. The method of claim 2 wherein said compound is d-2-(6-methoxy-2-naphthyl)propionic acid.

6. The method of claim 2 wherein said compound is l-2-(6-methoxy-2-naphthyl)propionic acid.

7. The method of claim 1 wherein said pregnant mammal is a woman who is not suffering from inflammation, pyrexia or non-parturition-causing pain but who is experiencing uterine muscle contractions. said compound being administered in a therapeutically effective amount adapted to reduce the intensity or duration of the uterine muscle contractions, or stop the uterine muscle contractions altogether, whereby termi nation of the pregnancy is postponed from the time it otherwise would have happened.

8. The method of claim 7 wherein said compound is dl-2-(6-methoxy-2-naphthyl)propionic acid.

9. The method of claim 7 wherein said compound is d-2-(6-methoxy-2-naphthyl)propionic acid.

10. The method of claim 2 wherein said compound is l-2-(6-methoxy-2-naphthyl)propionic acid. 

1. A METHOD COMPRISING ADMINISTERING TO A PREGNANT MAMMAL A COMPOUND SELECTED FROM THE GROUP OF COMPOUNDS REPRESENTED BY THE FORMULA:
 2. The method of claim 1 wherein said pregnant mammal is a woman who is not suffering from inflammation, pyrexia, or pain, said compound being administered in a therapeutically effective amount adapted to delay the onset of parturition.
 3. The method of claim 2 wherein said pregnant woman has had a spontaneous abortion, miscarriage or premature delivery which occurred prior to the time for normal parturition at or about full term.
 4. The method of claim 2 wherein said compound is dl-2-(6-methoxy-2-Naphthyl)propionic acid.
 5. The method of claim 2 wherein said compound is d-2-(6-methoxy-2-naphthyl)propionic acid.
 6. The method of claim 2 wherein said compound is 1-2-(6-methoxy-2-naphthyl)propionic acid.
 7. The method of claim 1 wherein said pregnant mammal is a woman who is not suffering from inflammation, pyrexia or non-parturition-causing pain but who is experiencing uterine muscle contractions, said compound being administered in a therapeutically effective amount adapted to reduce the intensity or duration of the uterine muscle contractions, or stop the uterine muscle contractions altogether, whereby termination of the pregnancy is postponed from the time it otherwise would have happened.
 8. The method of claim 7 wherein said compound is dl-2-(6-methoxy-2-naphthyl)propionic acid.
 9. The method of claim 7 wherein said compound is d-2-(6-methoxy-2-naphthyl)propionic acid.
 10. The method of claim 2 wherein said compound is 1-2-(6-methoxy-2-naphthyl)propionic acid. 